we proposed to develop a novel drug, 4-CI-KYN to treat neuropathic pain. 4-CI-KYN is a pro-drug of 7-Chlorokynurenic acid (7-Cl-KYNA), a chlorinated analogue of kynurenic acid, which is a natural neuromodulator and one of the most potent and specific GlyB antagonists known to man, which blocks glutamate transmission through the NMDA receptor. This receptor is important in mediating pain transmission, and drugs that block NMDA receptor produce analgesia. However, direct acting NMDA antagonists produce a number of side effects which have limited their therapeutic utility. In contrast, GlyB antagonists inhibit NMDA receptor function, reduce hyperalgesia and allodynia in neuropathic pain models, and have fewer side effects than classic NMDA receptor antagonists, making them a safer alternative as analgesics. 7-Cl-KYNA prevents excitotoxic and ischemic neuronal damage but like most GlyB antagonists does not cross the blood-brain barrier. 4-Cl-KYN, on the other hand, readily gains access to the brain following systemic administration and is efficiently converted to 7-Cl-KYNA specifically in brain areas with neuronal injury, and many believe that the hyperalgesia and allodynia associated with neuropathies originate from nerve damage or persistent activation and remodeling. Consequently, 4-Cl-KYN has a highly focused site of conversion in the CNS and spinal cord, and local concentrations of newly formed 7-Cl-KYNA are greatest at the site of therapeutic need. This reduces the level of systemic drug needed, and lowers the risk of side effects with long-term use of the drug. In our Phase I SBIR grant we showed that 4-Cl-KYN, which we refer to as AV-101, has potent antihyperalgesic actions in three models of peripheral tissue inflammation and nerve injury with no evidence of side effects. These preclinical studies support the efficacy of AV101 as an anti-hyperalgesic and its usefulness as a potential treatment of neuropathic pain. In subsequent studies, VistaGen developed an oral formulation of AV-101, conducted ADME analysis and subjected AV-101 to safety and toxicological assessments. Overall AV-101 is well tolerated, produces no safety or toxicity at doses that produce antihyperalgesic effects in animal models. Following on a positive pre-IND meeting with the FDA, we propose in this Phase II SBIR grant to conduct initial Phase 1 clinical safety evaluation of AV-101. The initial focus for our clinical development of AV-101 will be for the treatment of pain associated with human immunodeficiency virus-associated sensory neuropathy (HIV-SN). To begin the initial human testing of AV-101, we propose to conduct safety and pharmacokinetic studies in healthy human volunteers after single dose and repeated dosing of AV-101 to assess the maximum tolerated dose and the pharmacokinetic profiles of AV-101. AV-101 will also be tested in two pain models for efficacy in healthy human volunteers to gain an initial assessment of potential efficacy. These studies will provide the basis for Phase 2 clinical testing of AV-101 in treating neuropathic pain. PUBLIC HEALTH RELEVANCE: The goal of the proposed project is to test the safety of AV-101 in healthy human volunteers in Phase I clinical trials, and to also generate preliminary data on AV-101's potential efficacy. VistaGen is focused on developing AV-101 as a treatment for neuropathic pain and other neurodegenerative disorders. Positive results from this study will serve as a basis for further development of AV-101 in Phase II trials for treatment of neuropathic pain.